EP0761650B1 - Modification cristalline thermostable et supportant le stockage du N-méthyle-N-((1S)-1-phényle-2-((3S)-3-hydroxypyrrolidin-1-yl)-éthyle)-2,2-diphényle-acétamide et procédé pour sa préparation - Google Patents

Modification cristalline thermostable et supportant le stockage du N-méthyle-N-((1S)-1-phényle-2-((3S)-3-hydroxypyrrolidin-1-yl)-éthyle)-2,2-diphényle-acétamide et procédé pour sa préparation Download PDF

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Publication number
EP0761650B1
EP0761650B1 EP96112489A EP96112489A EP0761650B1 EP 0761650 B1 EP0761650 B1 EP 0761650B1 EP 96112489 A EP96112489 A EP 96112489A EP 96112489 A EP96112489 A EP 96112489A EP 0761650 B1 EP0761650 B1 EP 0761650B1
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EP
European Patent Office
Prior art keywords
hydroxypyrrolidin
pain
phenyl
ethyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96112489A
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German (de)
English (en)
Other versions
EP0761650A1 (fr
Inventor
Inge Dr. Stein
Holger Beeres
Klaus Dr. Beschmann
Steffen Dr. Neuenfeld
Andrew Dr. Barber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tioga Pharmaceuticals Inc
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to SI9630392T priority Critical patent/SI0761650T1/xx
Publication of EP0761650A1 publication Critical patent/EP0761650A1/fr
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Publication of EP0761650B1 publication Critical patent/EP0761650B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to a new thermostable form of N-methyl-N - [(1 S -) - 1-phenyl-2 - ((3S) -3-hydroxypyrrolidin1-yl -) - ethyl] -2,2-diphenyl-acetamide and a method of manufacture and isolation this connection in this new form as well as the use for Manufacture of medicinal products containing this compound and / or one contain their physiologically acceptable salts.
  • the object of the invention was therefore to N-methyl-N - [(1S -) - 1-phenyl-2 - ((3S) -3-hydroxypyrrolidin1-yl -) - ethyl] -2,2-diphenyl-acetamide in thermostable To provide form and a method of manufacture to provide this connection, creating a thermostable Product is obtained, which is stable in storage and for the production of Drug formulations are suitable.
  • the object of the invention is thus thermodynamically stable, storable N-methyl-N - [(1S -) - 1-phenyl-2 - ((3S) -3-hydroxypyrrolidin1-yl -) - ethyl] -2,2-diphenyl-acetamide with a melting point of 220-225 ° C and its use as a medicament for treatment inflammatory bowel diseases also pharmaceutical preparations, that contain this compound as a component and therefore for the effective treatment of inflammatory bowel diseases and the associated disease symptoms, as well as for the treatment of severe pain, especially hypersensitivity to pain, can be used.
  • the invention also relates to the use of this compound as a medicine to treat pain and Hypersensitivity to pain occurring in back problems, burn injuries, Sunburn and rheumatic diseases, as well inflammatory reactions that occur.
  • Subject of the invention is also the use of this medicine for treatment postoperative pain, hypersensitivity reactions, and that which often occurs after abdominal surgery Ileus.
  • Another object of the invention is the use of corresponding compound in drug formulations for treatment of neurodermatitis.
  • the compound of the invention and its physiologically acceptable Salts show particularly good analgesic effects.
  • connection according to the invention is in contrast to others Compounds with a similar spectrum of activity are particularly suitable for use in pharmaceutical preparations for treatment inflammatory bowel disease, as well as being analgesic and antiinflammatory effect is appropriate due to the disease normalize disorders of the intestinal motor system. In particular, it is suitable to get the bowel movements back in Get going when an inflammatory bowel disease occurs Intestinal obstruction threatens or has already occurred. This too can Effect for the treatment of a postoperative ileus and the associated associated pain.
  • connection according to the invention has changed due to that described above pharmacological effectiveness as particularly suitable proven in the treatment of burns, both of burns from heat or flame as well from severe sunburns.
  • these can Indications through the administration of suitable pharmaceutical Preparations containing the active ingredient according to the invention, in addition to the actual pain and pain hypersensitivity reactions influence inflammatory processes.
  • Also can be the reflective one that occurs in severe burns Prevent or treat lleus.
  • this active ingredient has proven to be particularly effective in treatment rheumatic diseases and back problems proven.
  • Type I is a Solvat. This shape easily changes to another crystal type um, which is referred to as Type II in the following text. With slow Heating of Type I involves solvent delivery. Subsequently correspond to the data of X-ray diffractometry, IR analysis and the melting point of those of type II.
  • Type III A form referred to as Type III is obtained when Type II is below extreme conditions with a humidity of around 73 to 95% is stored.
  • a modification characterized in the following as type IV has compared to that of Type II has a melting range of about 220-226 ° C and a heat of fusion of about 120-128 J / g.
  • thermodynamically stable Crystal modification is present, the two crystal modifications obtained II and IV are monotropic to each other.
  • thermodynamically stable crystal modification (mp. 196-200 ° C) obtained melt crystallized from 210 ° C to -78 ° C and stored at -78 ° C for 5 hours slowly the thermostable connection (221-226 ° C).
  • thermostable crystal modification IV After seven months of storage after that in the previous application Process described in DE 4215213 A1 Compound at room temperature could start converting for thermostable crystal modification IV. That is, the method described in this invention produced connection is in contrast to the other crystal modification stable in storage.
  • crystallization type IV is obtained when the reaction of the starting materials 1 - [(1S) -3-hydroxypyrrolidin-1-yl] - (2S) -2-methylamino-2-phenyl-ethane and diphenylacetyl chloride low temperatures, especially at -5 to 10 ° C, preferred at 0 to 8 ° C.
  • the molar ratio of the starting materials 1 - [(1S) -3-hydroxypyrrolidin-1-yl] - (2S) -2-methylamino-2-phenyl-ethane and diphenylacetyl chloride to each other 1: 0.75 to 1: 1.65, preferably 1: 1.1 to 1: 1.3.
  • the molar ratio of the starting compounds 1 - [(1S) -3-hydroxypymolidin-1-yl] - (2S) -2-methylamino-2-phenylethane and Diphenylacetyl chloride to the solvent used should be used be chosen so that the starting materials are in solution, the solvent but if possible only in a slight excess. Becomes Tetrahydrofuran chosen as the solvent, it has proven to be advantageous proven if the molar ratio of the above Educts and the solvent to each other about (0.8-1.2) :( 0.9-1.3) :( 14-22) is. A relationship has proven to be particularly effective from (0.9-1.1) :( 1-1.2) :( 16-19).
  • the compound of the invention and its physiologically acceptable Salts can therefore be used to manufacture pharmaceutical preparations be used by using them together with at least a carrier or auxiliary and, if desired, with an or several other active ingredients in the appropriate dosage form brings.
  • the preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine.
  • carrier substances are organic or inorganic substances in question, which is for the enteral (e.g. oral or rectal) or parenteral Suitable application and not with the compound of the invention react, for example water, vegetable oils, benzyl alcohols, Polyethylene glycols, glycerol triacetate and other fatty acid glycerides, Gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, Talc or cellulose.
  • Tablets coated tablets, Capsules, syrups, juices or drops. are of special interest Coated tablets and capsules with enteric coatings or Capsule shells. Suppositories are used for rectal use and parenteral ones Application solutions, preferably oily or aqueous Solutions, also suspensions, emulsions or implants.
  • the active ingredient claimed according to the invention can also be lyophilized and the lyophilizate obtained z. B. for the production of injectables be used.
  • the specified preparations can be sterilized and / or Auxiliaries such as preservatives, stabilizers and / or wetting agents, Emulsifiers, salts to influence the osmotic pressure, Contain buffer substances, colors and / or flavorings.
  • You can, if desired, also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
  • the compound of the invention is usually analogous to other known commercially available for the claimed indications Preparations administered, preferably in doses between about 1 mg and 50 mg, in particular between 5 and 30 mg per dosage unit.
  • the daily dosage is preferably between approximately 0.02 and 20 mg / kg, in particular 0.2 and 0.4 mg / kg Body weight.
  • the specific dose for each individual patient depends on various factors, such as age, body weight, general state of health, gender, of which Food, the time and route of administration, the rate of excretion, Drug combination and severity of each Disease to which the therapy applies.
  • the oral application is preferred.
  • Example A Injection glasses
  • a solution of 100 g active ingredient and 5 g disodium hydrogen phosphate are in 3 I double distilled water with 2 N hydrochloric acid adjusted to pH 6.5, sterile filtered, in injection glasses filled, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of active ingredient is melted 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of active ingredient 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of NA 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation.
  • 500 mg of active ingredient are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg talc and 0.1 kg magnesium stearate is added in the usual way Tablets pressed in such a way that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E Analogously to Example E, tablets are pressed, which are then made in the usual manner Way with a coating of sucrose, potato starch, Talc, tragacanth and dye are coated.
  • a solution of 1 kg of active ingredient in 60 l of double distilled water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Claims (9)

  1. Chlorhydrate du N-méthyl-N-[(1S-)-1-phényl-2-((3S)-3-hydroxypyrrolidine-1-yl-)-éthyl]-2,2-diphénylacétamide sous sa forme cristalline thermodynamiquement stable, ayant un point de fusion de 220-225°C.
  2. Médicament contenant un composé selon la revendication 1.
  3. Utilisation du médicament selon la revendication 2 pour préparer des formulations médicamenteuses ayant un effet pharmacologique en tant qu'agoniste des κ-opiacés.
  4. Utilisation du médicament selon la revendication 2 pour préparer des formulations médicamenteuses destinées au traitement des maladies inflammatoires de l'intestin.
  5. Utilisation du médicament selon la revendication 2 pour préparer des formulations médicamenteuses destinées au traitement des douleurs et de l'hypersensibilité à la douleur apparaissant lors des maux de dos.
  6. Utilisation du médicament selon la revendication 2 pour préparer des formulations médicamenteuses destinées au traitement des douleurs, de l'hypersensibilité à la douleur et des réactions inflammatoires en présence de maladies rhumatismales, de brûlures, de coups de soleil ou d'une névrodermite.
  7. Utilisation du médicament selon la revendication 2 pour préparer des formulations médicamenteuses destinées au traitement des douleurs postopératoires, de l'hypersensibilité à la douleur et de l'iléus post-opératoire.
  8. Préparation pharmaceutique, caractérisée en ce qu'elle contient un médicament selon la revendication 2.
  9. Procédé de préparation du chlorhydrate du N-méthyl-N-[(1S-)-1-phényl-2-((3S)-3-hydroxypyrrolidine-1-yl-)-éthyl]-2,2-diphénylacétamide selon la revendication 1, caractérisé en ce que.
    a) on fait réagir l'un avec l'autre à de basses températures, en particulier de -5 à 10°C, du 1-[(1S)-3-hydroxypyrrolidine-1-yl]-(2S)-2-méthylamino-2-phényléthane et du chlorure de diphénylacétyle, ce pour quoi
    b) tout en conservant la température, on ajoute lentement du chlorure de diphénylacétyle dissous dans un solvant, au 1-[(1S)-3-hydroxy-pyrrolidine-1-yl]-(2S)-2-méthylamino-2-phényléthane, dissous dans le même solvant et déjà en place dans l'appareillage, et
    c) après la réaction, on recristallise à chaud dans un solvant le produit brut obtenu.
EP96112489A 1995-08-26 1996-08-02 Modification cristalline thermostable et supportant le stockage du N-méthyle-N-((1S)-1-phényle-2-((3S)-3-hydroxypyrrolidin-1-yl)-éthyle)-2,2-diphényle-acétamide et procédé pour sa préparation Expired - Lifetime EP0761650B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9630392T SI0761650T1 (en) 1995-08-26 1996-08-02 Thermally stable and storable crystalline modification of N-methyl-N-((1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl)-2,2-diphenyl-acetamide and process for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19531464 1995-08-26
DE19531464A DE19531464A1 (de) 1995-08-26 1995-08-26 N-Methyl-N-[(1S-)-1-phenyl-2-((3S)-3-hydroxypyrrolidin 1-yl-)-ethyl]-2,2-diphenyl-acetamid

Publications (2)

Publication Number Publication Date
EP0761650A1 EP0761650A1 (fr) 1997-03-12
EP0761650B1 true EP0761650B1 (fr) 2001-10-31

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EP96112489A Expired - Lifetime EP0761650B1 (fr) 1995-08-26 1996-08-02 Modification cristalline thermostable et supportant le stockage du N-méthyle-N-((1S)-1-phényle-2-((3S)-3-hydroxypyrrolidin-1-yl)-éthyle)-2,2-diphényle-acétamide et procédé pour sa préparation

Country Status (25)

Country Link
US (1) US6060504A (fr)
EP (1) EP0761650B1 (fr)
JP (3) JP5023273B2 (fr)
KR (1) KR100436254B1 (fr)
CN (1) CN1081631C (fr)
AR (1) AR004679A1 (fr)
AT (1) ATE207895T1 (fr)
AU (1) AU716615B2 (fr)
BR (1) BR9603540A (fr)
CA (1) CA2184049C (fr)
CZ (1) CZ287783B6 (fr)
DE (2) DE19531464A1 (fr)
DK (1) DK0761650T3 (fr)
ES (1) ES2165948T3 (fr)
HU (1) HU226667B1 (fr)
MX (1) MX9603606A (fr)
NO (1) NO307048B1 (fr)
PL (1) PL187691B1 (fr)
PT (1) PT761650E (fr)
RU (1) RU2174976C2 (fr)
SI (1) SI0761650T1 (fr)
SK (1) SK282437B6 (fr)
TW (1) TW513407B (fr)
UA (1) UA41978C2 (fr)
ZA (1) ZA967200B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
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US8877800B2 (en) 2007-03-30 2014-11-04 Tioga Pharmaceuticals, Inc. Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome

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AU1828399A (en) * 1997-12-22 1999-07-12 Alza Corporation Novel formulations for the transdermal administration of asimadoline
DE19827633A1 (de) * 1998-04-20 1999-10-21 Merck Patent Gmbh Verfahren zur Herstellung von enantiomerenreinem N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamid
US6174878B1 (en) * 1999-08-31 2001-01-16 Alcon Laboratories, Inc. Topical use of kappa opioid agonists to treat otic pain
DE10116978A1 (de) * 2001-04-05 2002-10-10 Merck Patent Gmbh Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase
CN100411618C (zh) * 2002-05-17 2008-08-20 迪欧加药品公司 有效的选择性阿片受体调制剂化合物的用途
DE10259245A1 (de) * 2002-12-17 2004-07-01 Merck Patent Gmbh Derivate des Asimadolins mit kovalent gebundenen Säuren
EP1680115A1 (fr) * 2003-10-30 2006-07-19 Tioga Pharmaceuticals, Inc. Utilisation de modulateurs selectifs des recepteurs des opiaces en traitement d'une neuropathie
EP2284987B1 (fr) * 2009-08-12 2019-02-06 Braun GmbH Procédé et dispositif de réglage de la fréquence du courant de commande d'un moteur électrique
MX2012011604A (es) * 2010-04-07 2013-02-27 Onyx Therapeutics Inc Inhibidor de inmunoproteasoma de péptido epoxicetona cristalino.
US9675587B2 (en) 2013-03-14 2017-06-13 Allergan Holdings Unlimited Company Opioid receptor modulator dosage formulations
CN103664727A (zh) * 2013-12-19 2014-03-26 无锡万全医药技术有限公司 一种一锅法制备1-[(3s)-3-羟基吡咯烷-1-基]-(2s)-2-甲氨基-2-苯基乙烷的工艺
EP3558300B1 (fr) * 2016-12-21 2021-11-24 Tioga Pharmaceuticals, Inc. Formulations pharmaceutiques solides d'asimadoline
EP3932390A1 (fr) 2020-07-02 2022-01-05 Dr. August Wolff GmbH & Co. KG Arzneimittel Formulation de gel topique contenant de l'asimadoline

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DE4215213A1 (de) * 1992-05-09 1993-11-11 Merck Patent Gmbh Arylacetamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877800B2 (en) 2007-03-30 2014-11-04 Tioga Pharmaceuticals, Inc. Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome

Also Published As

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AR004679A1 (es) 1999-03-10
CN1081631C (zh) 2002-03-27
TW513407B (en) 2002-12-11
US6060504A (en) 2000-05-09
UA41978C2 (uk) 2001-10-15
CZ243496A3 (en) 1997-03-12
DK0761650T3 (da) 2002-02-18
NO307048B1 (no) 2000-01-31
MX9603606A (es) 1997-03-29
ZA967200B (en) 1997-03-03
AU716615B2 (en) 2000-03-02
ATE207895T1 (de) 2001-11-15
HUP9602346A3 (en) 1998-01-28
SK282437B6 (sk) 2002-02-05
DE59608050D1 (de) 2001-12-06
RU2174976C2 (ru) 2001-10-20
NO963526D0 (no) 1996-08-23
AU6214996A (en) 1997-03-06
KR100436254B1 (ko) 2005-01-25
JP2009046501A (ja) 2009-03-05
ES2165948T3 (es) 2002-04-01
SK108996A3 (en) 1997-06-04
CZ287783B6 (en) 2001-02-14
PL187691B1 (pl) 2004-09-30
CN1151986A (zh) 1997-06-18
SI0761650T1 (en) 2002-04-30
HUP9602346A2 (en) 1997-09-29
JP5023273B2 (ja) 2012-09-12
HU9602346D0 (en) 1996-10-28
BR9603540A (pt) 1998-05-12
JPH09110830A (ja) 1997-04-28
NO963526L (no) 1997-02-27
PL315799A1 (en) 1997-03-03
CA2184049A1 (fr) 1997-02-27
HU226667B1 (en) 2009-06-29
KR970010744A (ko) 1997-03-27
CA2184049C (fr) 2007-10-02
PT761650E (pt) 2002-04-29
JP2012246321A (ja) 2012-12-13
EP0761650A1 (fr) 1997-03-12
DE19531464A1 (de) 1997-02-27

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